Acriflavine-empowered IR780-PTX albumin nanoparticles for reinforced synergistic photochemotherapy

Traditional chemotherapy and radiotherapy for glioma are challenging due to the hypoxia in tumor microenvironment and the inability of chemotherapeutic agents to enter into tumor cells. Phototherapy is a novel therapeutic approach against various tumors in recent years. When combined with chemotherapy, the antitumor efficacy of phototherapy is superior than each alone. However, the combination of chemotherapy and phototherapy is still hampered by the hypoxic tumor microenvironment which upregulates the expression of hypoxia-inducible factor 1 (HIF-1) and its downstream pathways, as well as the thermoresistance caused by the overexpression of heat shock proteins (HSPs). To solve this, the biocompatible albumin-based nanoparticles (NPs) are developed to co-deliver IR780 iodine (IR780) and paclitaxel (PTX) simultaneously at an optimized ratio (IR780-PTX NPs) for synergistic photochemotherapy. Moreover, acriflavine (ACF), a chemical inhibitor of HIF-1, is formulated into intratumorally formed hydrogels to reinforce synergistic photochemotherapy. The continuously released ACF from hydrogel not only relieves the impact of photodynamic therapy-exacerbated tumor hypoxia by suppressing HIF-1 activity, but also efficiently attenuates HSP70 upregulation. The collaboration between IR780-PTX NPs and ACF hydrogels leads to an extraordinary antitumor effect in vitro and in vivo. The reinforced synergistic photochemotherapy via a single molecule by overcoming HIF-1 activity and HSP overexpression provides an effective therapeutic example to treat tumors, especially in those undergone severe hypoxia and/or therapy-induced thermoresistance.